While coordinated activities of the sympathetic and neuroendocrine systems are essential for proper maintenance of cardiovascular (CV) homeostasis, sustained sympathohumoral activation is highly detrimental, contributing to CV disorders including hypertension. Thus, elucidating mechanisms regulating sympathohumoral activation is critical for the prevention and more efficient treatment of hypertension. The hypothalamic paraventricular (PVN) nucleus plays pivotal roles in the generation of sympathohumoral responses. Neuronal activity within this nucleus is controlled by a balance between intrinsic properties and extrinsic synaptic inputs. In recent studies, we showed that the A-type K+ current (IA) inhibits PVN firing activity, and that blunted IA function contributes to enhanced neuronal activity in hypertension. Another major pathogenic factor in hypertension is increased glutamate NMDA receptor function. However, whether these two distinct mechanisms are functionally and causally coupled, is at present unknown. Using a multidisciplinary approach combining in vitro and in vivo studies, we obtained exciting preliminary data supporting a causal link between extrasynaptic NMDARs and IA in mediating increased neuronal activity and sympathoumoral activation in hypertension. Moreover we found astrocytes to be pivotal players influencing the efficacy of the eNMDAR-IA coupling. In this proposal, we will test the central hypothesis that over-activation of eNMDARs and its negative coupling to IA is a major contributing factor underlying increased neuronal activity and sympathohumoral activation in hypertension. The main objective of this application is to characterize the signaling mechanisms underlying the eNMDAR-IA coupling. Moreover, we aim to elucidate the relative contribution of (a) altered glial function and (b) intrinsic neuronal mechanisms to overactivation of the eNMDAR-IA coupling, and increased neuronal activity and sympathohumoral activation in hypertensive rats. Using a renovascular hypertensive animal model, we propose the following Specific Aims: Aim 1- To characterize the functional coupling between eNMDARs and IA; Aim 2- To determine if altered glial function contributes to enhanced eNMDAR-IA coupling in hypertensive rats; and Aim 3- To determine if altered neuronal mechanisms contribute to enhanced eNMDAR-IA coupling in hypertensive rats. We expect this work to expand our knowledge on basic neurobiological principles implicated in the generation of homeostatic neurohumoral responses. More importantly, we expect to identify key pathophysiological brain mechanisms contributing to maldaptive neurohumoral responses in hypertension. We hope our work will help in the development of novel and more efficient therapeutic strategies for the treatment of hypertensive conditions. PUBLIC HEALTH RELEVANCE: Hypertension is a major public health problem in the USA, is characterized by increased activity of the autonomic and neuroendocrine system (neurohumoral activation), which strongly influences morbidity and mortality in these patients. However, the precise mechanisms underlying neurohumoral remain unknown. In this proposal, we will use a multidisciplinary approach to test a series of novel hypothesis that aim to elucidate signaling mechanisms within the central nervous system that contribute to neurohumoral activation in hypertension. We expect our work to provide novel information on mechanisms underlying altered neuronal function in hypertensive patients, and to help in the development of novel and more efficient therapeutic strategies for the treatment of prevalent complications in hypertension.